4-Pyridone-3-carboxylic acid derivatives

ABSTRACT

The invention relates to 4-pyridone-3-carboxylic acid derivatives, a process for the preparation thereof and pharmaceutical compositions containing same. The 4-pyridone-3-carboxylic acid derivatives are useful as antibacterial agents and/or as agents having a stimulating activity on the central nervous system.

This is a continuation of application Ser. No. 187,878 filed Sept. 17,1980, now abandoned, which is a continuation of application Ser. No.002,474, filed Jan. 10, 1979, now abandoned.

BRIEF SUMMARY OF THE INVENTION

The 4-pyridone-3-carboxylic acid derivatives of the invention arecompounds of the formula ##STR1## wherein R¹, R² and R³ are ashereinafter described, and salts thereof.

In another aspect, the invention relates to intermediates of the formula##STR2## wherein R¹, R² and R³ are as hereinafter described.

DETAILED DESCRIPTION OF THE INVENTION

The 4-pyridone-3-carboxylic acid derivatives of the invention arecompounds of the formula ##STR3## wherein R¹ is C₁₋₈ -alkyl, C₃₋₁₀-cycloalkyl, C₃₋₁₀ -cycloalkylC₁₋₆ -alkyl, C₁₋₆ -alkoxy or C₁₋₆-alkoxy-C₁₋₆ -alkyl; R² is hydrogen or C₁₋₆ -alkyl; R³ is phenyl,phenethyl or styryl, which are optionally substituted by R⁴, R⁵ and/orR⁶, or an aromatic heterocyclic 6-membered ring containing one or moreN-atoms, which is linked via a ring C-atom and which is optionallysubstituted by R⁷ ; R⁴ and R⁵ each, independently, are halogen,trifluoromethyl, hydroxy, C₁₋₆ -alkoxy, C₁₋₆ -alkylthio, C₁₋₆ -alkyl,amino, acylamino, C₁₋₆ -alkylamino, di-C₁₋₆ -alkylamino, nitro or a5-membered or 6-membered heterocycle linked via a ring N- or C-atom orR⁴ and R⁵, taken together, are C₁₋₆ -alkylenedioxy; R⁶ is C₁₋₆ -alkoxy;and R⁷ is halogen, hydroxy, C₁₋₆ -alkoxy, C₁₋₆ -alkylthio, C₁₋₆ -alkyl,amino, C₁₋₆ -alkylamino or di-C₁₋₆ -alkylamino; provided that R² is C₁₋₆-alkyl when R¹ is methyl and simultaneously R³ is phenyl,

and salts thereof.

According to the process of the invention, the aforesaid4-pyridone-3-carboxylic acid derivatives, that is, the compounds offormula I hereinbefore and their salts, are prepared by

(a) dehydrogenating a 1,4,5,6-tetrahydronicotinic acid derivative of theformula ##STR4## wherein R¹, R² and R³ are as previously described, inthe 5,6-position, or

(b) modifying a substituent R² and/or R³ in a known manner within thedefinitions given earlier, and, if desired, converting a compound offormula I obtained into a salt, especially physiologically orpharmaceutically acceptable salts.

Exemplary of C₁₋₈ -alkyl, which can be straight-chain or branched-chain,are methyl, ethyl, propyl, isopropyl, butyl, sec.butyl, tert.butyl,octyl or the like; methyl and ethyl are preferred. Exemplary of C₁₋₆-alkylenedioxy are methylenedioxy and ethylenedioxy and the like.Cyclopropyl is a preferred C₃₋₁₀ -cycloalkyl. The term "halogen"includes fluorine, chlorine, bromine and iodine. Exemplary of aromaticheterocyclic 6-membered rings containing one or more N-atoms denoted byR³ are 2-, 3- or 4-pyridyl, 3- or 4-pyridazyl, 2-, 4- or 5-pyrimidyl, 2-or 3-pyrazyl and the like. When R⁴ and/or R⁵ are a 5-membered or6-membered heterocycle linked via a ring N- or C-atom, they can be, forexample, a pyrrole, pyrroline, pyrrolidine, isoxazole, oxazole,thiophene, thiazole, pyrazole, imidazole, imidazoline, imidazolidine,triazole, oxadiazole, pyridine, piperidine, morpholine, piperazine,thiazine, pyridazine, pyrimidine, triazine or the like. The acyl groupin an acylamino is preferably derived from an aliphatic carboxylic acid,such as, an acid containing 1-6 carbon atoms, for example, formic acid,acetic acid, propionic acid, or the like.

Compounds of formula I wherein R² is hydrogen form alkali metal,alkaline earth metal and ammonium salts, the latter being optionallysubstituted. When basic substituents are present in the molecule, thecompounds of formula I form addition salts with physiologically orpharmaceutically compatible strong inorganic and organic acids, forexample, hydrochloric acid, sulfuric acid, phosphoric acid,methanesulfonic acid, paratoluenesulfonic acid, and the like.

Preferred compounds of formula I are those wherein R¹ is ethyl orpropyl, those wherein R² is hydrogen or methyl and those wherein R³ issubstituted phenyl, a substituent, especially a substituted amino or anitrogen-containing heterocycle, in the 4-position of said phenyl isespecially preferred.

The dehydrogenation of a 1,4,5,6-tetrahydronicotinic acid derivative offormula II in accordance with embodiment (a) of the process can becarried out according to known methods, conveniently with a substitutedbenzoquinone, such as, 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ)or tetrachloro-1,4-benzoquinone (chloranil) in an inert organic solventsuch as methylene chloride, toluene or dioxane and at a temperature inthe range of from room temperature up to the reflux temperature of themixture. In general, the dehydrogenation is carried out by adding asolution of the substituted benzoquinone dropwise to the solution of the1,4,5,6-tetrahydronicotinic acid derivative, care being taken to useequimolar amounts. Where colorless starting materials are used, the endof the dehydrogenation can readily be detected by the appearance of acolored mixture. The product can be isolated from the mixture in theusual manner and can be purified, for example, by recrystallization orchromatography.

In accordance with embodiment (b) of the process, a substituent R²and/or R³ can be modified in a known manner within the definitions givenearlier.

Thus, for example, the carboxyl group (R² =H) can be esterified or anester group (R² =C₁₋₆ -alkyl) can be saponified. An amino group presenton a substituent R³ can be alkylated, a nitro group can be reduced to anamino group, a hydroxy group can be etherified, an alkoxy group can becleaved or a halogen can be replaced by a different halogen or anotherfunctional group. Furthermore, a saturated heterocyclic substituent canbe dehydrogenated if desired, a partially or completely unsaturatedheterocycle can be hydrogenated or the styryl group can be hydrogenatedto the phenethyl group without the basic structure common to allcompounds provided by the invention thereby being altered.

The starting materials of formula II can be prepared, in accordance withthe invention, by heating a 2-(R¹ -aminomethylene)-3-oxo-4-pentenoicacid derivative of the formula ##STR5## wherein R¹ and R³ are aspreviously described, conveniently in an inert polar aprotic organicsolvent such as, for example, dimethylformamide (DMF), dimethylsulfoxide(DMSO) or hexamethylphosphoric acid triamide. The solution is heated ata temperature in the range of from about 100° C. up to the refluxtemperature for 1 to several hours, whereby ring closure to the1,4,5,6-tetrahydronicotinic acid derivative of formula II occurs.

The 2-(R¹ -aminomethylene)-3-oxo-4-pentenoic acid derivatives of formulaIII can be obtained in a known manner in a multi-stage synthesis fromaldehydes of the formula R³ --CHO.

The preparation of 1-ethyl-6-phenyl-4-oxo-1,4-dihydronicotinic acid frombenzaldehyde is generically described in the Formula Scheme whichfollows and the preparation of1-ethyl-6-(4-chlorophenyl)-4-oxo-1,4-dihydronicotinic acid and itsmethyl ester is described in detail in Example 1 hereinafter. ##STR6##

By varying the aldehyde of formula VII-1, the ester group of thetriphenylphosphonium compound or the amine which is reacted with acompound of formula IV-1 to give a derivative of formula III-1, inprinciple all compounds in accordance with the present invention can beprepared in an analogous manner.

The 1,4,5,6-tetrahydronicotinic acid derivatives of formula II and the2-(R¹ -aminomethylene)-3-oxo-4-pentenoic acid derivatives of formula IIIare novel and also form part of the present invention.

The compounds of formula I hereinbefore possess pharmacologicalactivity. More specifically, the compounds of formula I possessantibacterial activity and/or a stimulating activity on the centralnervous system. Further, said compounds have low acute toxicities. Thus,for example, 1-ethyl-4-oxo-6-phenyl-1,4-dihydronicotinic acid has asubstantially superior activity to nomifensin with about the same LD₅₀,and it shows advantage over d-amphetamine and d-methamphetamine byhaving a substantially lower LD₅₀ with about the same strong activity(see Table 1 hereinafter).

                  TABLE 1                                                         ______________________________________                                                                Turning rat test(1)                                   Compound    LD.sub.50   minimum active dosage                                 ______________________________________                                        1-Ethyl-4-oxo-6-                                                                          300-600 p.o.                                                                              1                                                     phenyl-1,4-                                                                   dihydronicotinic                                                              acid                                                                          Nomifensin  300-600 p.o.                                                                              3                                                     d-Amphetamine 1/2                                                                         35 p.o.,    1                                                     H.sub.2 SO.sub.4                                                                          14 i.v., 22 s.c.                                                  d-Methamphetamine                                                                         9.5 i.v., 14 s.c.                                                                         1                                                     HCl                                                                           ______________________________________                                         (1)Arch. int. Pharmacodyn. Ther. 217, 118-130 (1975)                     

With regard to the antibacterial activity of the compounds of formula I,they are especially suitable as therapeutic agents in urinary tractinfections. Vis-a-vis known compounds having this indication, forexample, nitrofurantoin, they possess an increased activity againstspecific causative organisms, such as, Escherichia coli (see Table 2hereinafter). In view of their central nervous system stimulatingactivity the compounds of formula I can be used, for instance, asanti-depressants.

                  TABLE 2                                                         ______________________________________                                                            Escherichia coli                                                                in vitro                                                                              in vivo                                                               MIC*    (mouse) ED.sub.50                               Compound              μg/ml                                                                              mg/kg p.o.                                      ______________________________________                                        Nitrofurantoin        5       >100                                            1-Ethyl-6-(4-methoxyphenyl)-4-oxo-                                                                  2.5     >100                                            1,4-dihydronicotinic acid                                                     1-Ethyl-6-(3,4-methylenedioxyphenyl)-                                                               2.5     >100                                            4-oxo-1,4-dihydronicotinic acid                                               1-Ethyl-6-(4-methylthiophenyl)-4-oxo-                                                               2.5     82                                              1,4-dihydronicotinic acid                                                     1-Ethyl-6-(4-pyrrolophenyl)-4-oxo-                                                                  1.2     34                                              1,4-dihydronicotinic acid                                                     1-Ethyl-6-(4-pyrrolidinophenyl)-4-                                                                  1.2     19                                              oxo-1,4-dihydronicotinic acid                                                 1-Ethyl-6-(4-dimethylaminophenyl)-4-                                                                0.6     8.8                                             oxo-1,4-dihydronicotinic acid                                                 1-Ethyl-6-(3-methyl-4-methylamino-                                                                  0.6     3.5                                             phenyl)-4-oxo-1,4-dihydronicotinic                                            acid                                                                          ______________________________________                                         *Minimum Inhibitory Concentration                                        

The 4-pyridone-3-carboxylic acid derivatives provided by the inventioncan therefore be used in the therapy and prophylaxis of infections,especially of bacterial infections, and for the stimulation of thecentral nervous system in the form of pharmaceutical preparations whichprovide for direct or delayed liberation of the active ingredient andwhich contain them in association with a carrier material. Such carriermaterial can be organic or inorganic inert carrier material suitable fororal, rectal or parenteral administration, for example, water, gelatin,gum arabic, lactose, starch, magnesium stearate, talc, vegetable oils,polyalkyleneglycols, petroleum jelly or the like. The pharmaceuticalpreparations can be made up in solid form, for example, as tablets,dragees, suppositories or capsules, in semi-solid form, for example, assalves, or in liquid form, for example, as solutions, suspensions oremulsions. The pharmaceutical preparations may be sterilized and/or maycontain adjuvants such as preserving, stabilizing, wetting oremulsifying agents, agents for flavor improvement, salts for varying theosmotic pressure or buffer substances.

The pharmaceutical preparations can be prepared in a known manner,namely, by mixing the active ingredient with non-toxic inert carriermaterials suitable for therapeutic administration and finishing theresulting mixture into a suitable galenical form.

As dosage guidelines for the compounds of formula I as an antibacterialagent there can be considered an amount of 10-100 mg/kg, preferablyabout 50 mg/kg, body weight per day, and as an agent having an activityon the central nervous system there can be considered an amount of 100μg-10 mg/kg.

The following Examples further illustrate the invention. Alltemperatures are stated in degrees Centigrade, unless otherwisementioned.

EXAMPLE 1 Preparation of1-ethyl-6-(4-chlorophenyl)-4-oxo-1,4-dihydronicotinic acid

3 g. of 1-ethyl-6-(4-chlorophenyl)-4-oxo-1,4,5,6-tetrahydronicotinicacid methyl ester were heated to 80° C. in 50 ml. of benzene and treateddropwise with a benzene solution of 4 g. of dichlorodicyanobenzoquinone(DDQ) until decolorization was no longer visible. The mixture was cooledand the crystalline material which thereby separated out was filteredoff under suction.

The resulting material, a mixture of1-ethyl-6-(4-chlorophenyl)-4-oxo-1,4-dihydronicotinic acid methyl esterwith DDQ, was stirred with 20 ml. of 1N sodium hydroxide at roomtemperature for 30 minutes, the clear solution was diluted with 50 ml.of ice-water and cautiously acidified to pH 6.5 with 0.5-N hydrochloricacid. In so doing, the product separated in almost pure form. It wasrecrystallized from ethyl acetate. There were obtained 2.1 g. of1-ethyl-6-(4-chlorophenyl)-4-oxo-1,4-dihydronicotinic acid having amelting point of 215°-217° C.

The starting material was prepared as follows:

14 g. of 4-chlorobenzaldehyde and 47 g. of[2-methoxy-3-(methoxycarbonyl)allyl]-triphenylphosphonium bromide weredissolved in 130 ml. of methylene chloride. 100 ml. of 50% aqueoushydroxide were allowed to flow into the resulting solution at roomtemperature while stirring well, a temperature increase being observed.The mixture was stirred for a further 20 minutes, poured on to ice andextracted with methylene chloride. The residue remaining after dryingover sodium sulfate and evaporation of the solvent was crystallized frommethanol, the mother liquor in hexane/ether (4:1 v/v) was filteredthrough a short silica gel column and the product crystallizing out fromthe eluate was combined with the main product. The total yield was 23.5g. of pure 5-(4-chlorophenyl)-3-methoxy-2,4-pentadienecarboxylic acidmethyl ester having a melting point of 69°-72° C.

23.5 g. of 5-(p-chlorophenyl)-3-methoxy-2,4-pentadienecarboxylic acidmethyl ester dissolved in 250 ml. of dioxane were treated with 150 ml.of 0.1-N sulfuric acid and held at 100° C. for 3 hours. The mixture wascooled down, extracted with ethyl acetate, dried and crystallized by theaddition of hexane. There were obtained 14.8 g. of5-(4-chlorophenyl)-3-oxo-4-pentenoic acid methyl ester having a meltingpoint of 78°-80° C.

14.8 g. of 5-(4-chlorophenyl)-3-oxo-4-pentenoic acid methyl ester weredissolved in 100 ml. of benzene and treated with N,N-dimethylformamidedimethylacetal. The red-brown colored solution was stirred at 60° C. for30 minutes, solvent and excess reagent were removed and there wasobtained 5-(4-chlorophenyl)-2-(dimethylaminomethylene)-3-oxo-4-pentenoicacid methyl ester in the form of a red-brown oil which was furtherprocessed in this form.

The oil obtained was dissolved in 50 ml. of benzene and stirred at roomtemperature for 30 minutes with 100 ml. of a saturated benzene solutionof ethylamine. Thereafter, the solvent was removed and the residue wascrystallized from ether/hexane. There were obtained 12.4 g. of2-(ethylaminomethylene)-5-(4-chlorophenyl)-3-oxo-4-pentenoic acid methylester having a melting point of 78°-80° C.

5.2 g. of 2-(ethylaminomethylene)-5-(4-chlorophenyl)-3-oxo-4-pentenoicacid methyl ester in 50 ml. of dimethylformamide were held at 140°-150°C. for 3 hours. After removal of the solvent, there was obtained1-ethyl-6-(4-chlorophenyl)-4-oxo-1,4,5,6-tetrahydronicotinic acid methylester in the form of a uniform oily residue.

In an analogous manner,

from benzaldehyde and propylamine there was obtained4-oxo-6-phenyl-1-propyl-1,4-dihydronicotinic acid having a melting pointof 153°-154° C.;

from benzaldehyde and isopropylamine there was obtained1-isopropyl-4-oxo-6-phenyl-1,4-dihydronicotinic acid having a meltingpoint of 215°-216° C.;

from benzaldehyde and butylamine there was obtained1-butyl-4-oxo-6-phenyl-1,4-dihydronicotinic acid having a melting pointof 119°-120° C.;

from benzaldehyde and tert.butylamine there was obtained1-tert.butyl-4-oxo-6-phenyl-1,4-dihydronicotinic acid having a meltingpoint of 295° C. (decomposition);

from benzaldehyde and octylamine there was obtained1-octyl-4-oxo-6-phenyl-1,4-dihydronicotinic acid having a melting pointof 62°-63° C.;

from benzaldehyde and cyclopropylmethylamine there was obtained1-(cyclopropylmethyl)-4-oxo-6-phenyl-1,4-dihydronicotinic acid having amelting point of 177°-179° C.;

from benzaldehyde and cyclopropylamine there was obtained1-cyclopropyl-4-oxo-6-phenyl-1,4-dihydronicotinic acid having a meltingpoint of 180°-181° C.;

from benzaldehyde and cyclopentylamine there was obtained1-cyclopentyl-4-oxo-6-phenyl-1,4-dihydronicotinic acid having a meltingpoint of 188°-190° C.;

from benzaldehyde and cyclohexylamine there was obtained1-cyclohexyl-4-oxo-6-phenyl-1,4-dihydronicotinic acid having a meltingpoint of 257°-259° C.;

from benzaldehyde and 1-adamantylamine there was obtained1-(1-adamantyl)-4-oxo-6-phenyl-1,4-dihydronicotinic acid having amelting point of 248° C. (decomposition);

from benzaldehyde and 2-methoxyethylamine there was obtained1-(2-methoxyethyl)-4-oxo-6-phenyl-1,4-dihydronicotinic acid having amelting point of 144°-146° C.;

from benzaldehyde and methoxylamine there was obtained1-methoxy-4-oxo-6-phenyl-1,4-dihydronicotinic acid having a meltingpoint of 193°-194° C.;

from benzaldehyde and O-butyl-hydroxylamine there was obtained1-butoxy-4-oxo-6-phenyl-1,4-dihydronicotinic acid having a melting pointof 130°-132° C.;

from 3-nitrobenzaldehyde and ethylamine there was obtained1-ethyl-6-(3-nitrophenyl)-4-oxo-1,4-dihydronicotinic acid having amelting point of 242°-243° C.;

from 3-aminobenzaldehyde and ethylamine there was obtained1-ethyl-6-(3-aminophenyl)-4-oxo-1,4-dihydronicotinic acid having amelting point of 145°-146° C.;

from 4-(dimethylamino)-benzaldehyde and methoxylamine there was obtained6-[4-(dimethylamino)-phenyl]-1-methoxy-4-oxo-1,4-dihydronicotinic acidhaving a melting point of 224° C. (decomposition);

from 4-(dimethylamino)-benzaldehyde and O-butylhydroxylamine there wasobtained1-butoxy-6-[4-(dimethylamino)-phenyl]-4-oxo-1,4-dihydronicotinic acidhaving a melting point of 155°-157° C.;

from 4-acetamido-benzaldehyde and ethylamine there was obtained6-(4-acetamidophenyl)-1-ethyl-4-oxo-1,4-dihydronicotinic acid having amelting point of 237.5°-239° C.;

from 3-(trifluoromethyl)-benzaldehyde and ethylamine there was obtained1-ethyl-6-[3-(trifluoromethyl)-phenyl]-4-oxo-1,4-dihydronicotinic acidhaving a melting point of 186°-188° C.;

from 4-(4-methylpiperazino)-benzaldehyde and ethylamine there wasobtained1-ethyl-6-[4-(4-methylpiperazino)-phenyl]-4-oxo-1,4-dihydronicotinicacid having a melting point of 246°-248° C.; and

from p-methoxycinnamaldehyde and ethylamine there was obtained1-ethyl-6-(p-methoxystyryl)-4-oxo-1,4-dihydronicotinic acid having amelting point of 237°-238° C.

EXAMPLE 2 Preparation of1-ethyl-6-(4-chlorophenyl)-4-oxo-1,4-dihydronicotinic acid

800 mg. of 1-ethyl-6-(4-chlorophenyl)-4-oxo-1,4,5,6-tetrahydronicotinicacid in 20 ml. of benzene were treated dropwise at 80° C. with asolution of 1.5 g. of dichlorodicyanobenzoquinone (DDQ) in 30 ml. ofbenzene until the solution was no longer decolorized. The mixture wascooled down, the precipitate was filtered off under suction, dissolvedin 20 ml. of 1N sodium hydroxide and the solution was cautiouslyacidified to pH 6.5 with cold 0.5-N hydrochloric acid. The separatedcolorless product was washed with water and then with ether. There wasobtained 0.7 g. of 1-ethyl-6-(4-chlorophenyl)-4-oxo-1,4-dihydronicotinicacid having a melting point of 214°-215° C.

The starting material was obtained by dissolving 1.85 g. of1-ethyl-6-(4-chlorophenyl)-4-oxo-1,4,5,6-tetrahydronicotinic acid methylester (prepared as described in Example 1) in 10 ml. of dioxane and 10ml. of methanol and heating the solution under reflux for 3 hours in thepresence of 20 ml. of 1-N sodium hydroxide. The mixture was cooled down,acidified with 0.5-N hydrochloric acid, the separated crystals werefiltered off under suction and recrystallized from methanol/ether. Yield1.3 g.; melting point 142°-144° C.

EXAMPLE 3 Preparation of 1-ethyl-4-oxo-6-phenyl-1,4-dihydronicotinicacid

In a manner analogous to that described in Examples 1 and 2, frombenzaldehyde there was obtained2-(ethylaminomethylene)-3-oxo-5-phenyl-4-pentenoic acid methyl ester,melting point 92°-94° C., this was cyclized and saponified to give1-ethyl-4-oxo-6-phenyl-1,4,5,6-tetrahydronicotinic acid, melting point148°-150° C., and this was subsequently dehydrogenated to give1-ethyl-4-oxo-6-phenyl-1,4-dihydronicotinic acid, melting point166°-167° C.

EXAMPLE 4 Preparation of1-ethyl-6-[4-dimethylamino)-phenyl]-4-oxo-1,4-dihydronicotinic acid

In a manner analogous to that described in Example 1, from4-(dimethylamino)benzaldehyde there was obtained2-(ethylaminomethylene)-5-[4-(dimethylamino)-phenyl]-3-oxo-4-pentenoicacid methyl ester, melting point 129°-130° C., this was cyclized to give1-ethyl-6-[4-(dimethylamino)-phenyl]-4-oxo-1,4,5,6-tetrahydronicotinicacid methyl ester, melting point 85°-87° C., and this was dehydrogenatedand saponified to give1-ethyl-6-[4-(dimethylamino)-phenyl]-4-oxo-1,4-dihydronicotinic acid,melting point 258°-259° C.

EXAMPLE 5 Preparation of1-ethyl-6-[3-methyl-4-(dimethylamino)-phenyl]-4-oxo-1,4-dihydronicotinicacid

In a manner analogous to that described in Example 1, from3-methyl-4-(dimethylamino)-benzaldehyde there was obtained2-(ethylaminomethylene)-5-[3-methyl-4-(dimethylamino)-phenyl]-3-oxo-4-pentenoicacid methyl ester, melting point 98°-100° C., this was cyclized to give1-ethyl-6-[3-methyl-4-(dimethylamino)-phenyl]-4-oxo-1,4,5,6-tetrahydronicotinicacid methyl ester, this was dehydrogenated to give1-ethyl-6-[3-methyl-4-(dimethylamino)-phenyl]-4-oxo-1,4-dihydronicotinicacid methyl ester, melting point 132°-134° C., and this was saponifiedto give1-ethyl-6-[3-methyl-4-(dimethylamino)-phenyl]-4-oxo-1,4-dihydronicotinicacid, melting point 160°-162° C.

EXAMPLE 6 Preparation of1-ethyl-6-(4-pyrrolophenyl)-4-oxo-1,4-dihydronicotinic acid

In a manner analogous to that described in Examples 1 and 2, from4-pyrrolobenzaldehyde there was obtained2-(ethylaminomethylene)-3-oxo-5-(4-pyrrolophenyl)-4-pentenoic acidmethyl ester, melting point 119°-121° C., this was cyclized andsaponified to give1-ethyl-6-(4-pyrrolophenyl)-4-oxo-1,4,5,6-tetrahydronicotinic acid andthis was subsequently dehydrogenated to give1-ethyl-6-(4-pyrrolophenyl)-4-oxo-1,4-dihydronicotinic acid, meltingpoint above 300° C.

EXAMPLE 7 Preparation of1-ethyl-6-(4-methoxyphenyl)-4-oxo-1,4-dihydronicotinic acid

In a manner analogous to that described in Examples 1 and 2, from4-methoxybenzaldehyde there was obtained2-(ethylaminomethylene)-3-oxo-5-(4-methoxyphenyl)-4-pentenoic acidmethyl ester, this was cyclized and saponified to give1-ethyl-6-(4-methoxyphenyl)-4-oxo-1,4,5,6-tetrahydronicotinic acid,melting point 173°-174° C., and this was subsequently dehydrogenated togive 1-ethyl-6-(4-methoxyphenyl)-4-oxo-1,4-dihydronicotinic acid,melting point 215°-217° C.

EXAMPLE 8 Preparation of1-cyclopropyl-6-(4-methoxyphenyl)-4-oxo-1,4-dihydronicotinic acid

In a manner analogous to that described in Examples 1 and 2, from4-methoxybenzaldehyde there was obtained2-(cyclopropylaminomethylene)-5-(4-methoxyphenyl)-3-oxo-4-pentenoic acidmethyl ester, melting point 125°-127° C., this was cyclized andsaponified to give1-cyclopropyl-6-(4-methoxyphenyl)-4-oxo-1,4,5,6-tetrahydronicotinicacid, melting point 137°-139° C., and this was subsequentlydehydrogenated to give1-cyclopropyl-6-(4-methoxyphenyl)-4-oxo-1,4-dihydronicotinic acid,melting point 159°-161° C.

EXAMPLE 9 Preparation of1-ethyl-6-(3,4-dimethoxyphenyl)-4-oxo-1,4-dihydronicotinic acid

In a manner analogous to that described in Examples 1 and 2, from3,4-dimethoxy-benzaldehyde there was obtained2-(ethylaminomethylene)-5-(3,4-dimethoxyphenyl)-3-oxo-4-pentenoic acidmethyl ester, this was cyclized to give1-ethyl-6-(3,4-dimethoxyphenyl)-4-oxo-1,4,5,6-tetrahydronicotinic acidmethyl ester, melting point 134°-135° C., this was saponified to give1-ethyl-6-(3,4-dimethoxyphenyl)-4-oxo-1,4,5,6-tetrahydronicotinic acid,melting point 182°-183° C., and this was subsequently dehydrogenated togive 1-ethyl-6-(3,4-dimethoxyphenyl)-4-oxo-1,4-dihydronicotinic acid,melting point 232°-234° C.

EXAMPLE 10 Preparation of1-ethyl-6-(3,4-methylenedioxyphenyl)-4-oxo-1,4-dihydronicotinic acid

In a manner analogous to that described in Examples 1 and 2, from3,4-methylenedioxy-benzaldehyde there was obtained2-(ethylaminomethylene)-5-(3,4-methylenedioxyphenyl)-3-oxo-4-pentenoicacid methyl ester, melting point 124°-125° C., this was cyclized andsaponified to give1-ethyl-6-(3,4-methylenedioxyphenyl)-4-oxo-1,4,5,6-tetrahydronicotinicacid, melting point 173°-175° C., and this was subsequentlydehydrogenated to give1-ethyl-6-(3,4-methylenedioxyphenyl)-4-oxo-1,4-dihydronicotinic acid,melting point 269°-270° C.

The last-mentioned acid was converted in a manner known per se into1-ethyl-6-(3,4-methylenedioxyphenyl)-4-oxo-1,4-dihydronicotinic acidmethyl ester, having a melting point of 183°-185° C.

EXAMPLE 11 Preparation of1-cyclopropyl-6-(3,4-methylenedioxyphenyl)-4-oxo-1,4-dihydronicotinicacid

In a manner analogous to that described in Examples 1 and 2, from3,4-methylenedioxy-benzaldehyde there was obtained2-(cyclopropylaminomethylene)-5-(3,4-methylenedioxyphenyl)-3-oxo-4-pentenoicacid methyl ester, melting point 158°-160° C., this was cyclized andsaponified to give1-cyclopropyl-6-(3,4-methylenedioxyphenyl)-4-oxo-1,4,5,6-tetrahydronicotinicacid, melting point 122°-124° C., and this was subsequentlydehydrogenated to give1-cyclopropyl-6-(3,4-methylenedioxyphenyl)-4-oxo-1,4-dihydronicotinicacid, melting point 211°-212° C.

EXAMPLE 12 Preparation of1-ethyl-4-oxo-6-(3,4,5-trimethoxyphenyl)-1,4-dihydronicotinic acid

In a manner analogous to that described in Examples 1 and 2,from3,4,5-trimethoxy-benzaldehyde there was obtained2-(ethylaminomethylene)-3-oxo-5-(3,4,5-trimethoxyphenyl)-4-pentenoicacid methyl ester in the form of an oil, this was cyclized to give1-ethyl-4-oxo-6-(3,4,5-trimethoxyphenyl)-1,4,5,6-tetrahydronicotinicacid methyl ester and this was subsequently dehydrogenated andsaponified to give1-ethyl-4-oxo-6-(3,4,5-trimethoxyphenyl)-1,4-dihydronicotinic acid,melting point 200°-201° C.

EXAMPLE 13 Preparation of1-ethyl-6-(4-methylthiophenyl)-4-oxo-1,4-dihydronicotinic acid

In a manner analogous to that described in Examples 1 and 2, from4-(methylthio)-benzaldehyde there was obtained2-(ethylaminomethylene)-5-(4-methylthiophenyl)-3-oxo-4-pentenoic acidmethyl ester, this was cyclized and saponified to give1-ethyl-6-(4-methylthiophenyl)-4-oxo-1,4,5,6-tetrahydronicotinic acid,melting point 173°-174° C., and this was subsequently dehydrogenated togive 1-ethyl-6-(4-methylthiophenyl)-4-oxo-1,4-dihydronicotinic acid,melting point 195°-197° C.

EXAMPLE 14 Preparation of1-ethyl-6-(4-hydroxyphenyl)-4-oxo-1,4-dihydronicotinic acid

In a manner analogous to that described in Examples 1 and 2, fromp-hydroxybenzaldehyde there was obtained2-(ethylaminomethylene)-5-(4-hydroxyphenyl)-3-oxo-4-pentenoic acidmethyl ester, this was cyclized and saponified to give1-ethyl-6-(4-hydroxyphenyl)-4-oxo-1,4,5,6-tetrahydronicotinic acid andthis was subsequently dehydrogenated to give1-ethyl-6-(4-hydroxyphenyl)-4-oxo-1,4-dihydronicotinic acid, meltingpoint 243°-245° C.

This acid can also be prepared as follows:

3.7 g. of a 50% sodium hydride dispersion are treated in 50 ml. ofdimethylformamide (DMF) at room temperature while stirring with 5 g. ofethylmercaptan. Subsequently, there is added thereto a solution of 4.3g. of 1-ethyl-6-(4-methoxyphenyl)-4-oxo-1,4-dihydronicotinic acid(prepared as described in Example 7) in 15 ml. of DMF and the mixture isheated to 100° C., a clear solution firstly being obtained. After about30 minutes, a precipitate is produced. The mixture is stirred at 100° C.for 16 hours, then cooled down and the mixture is taken up in ethylacetate. The resulting solution is washed neutral with cold 0.1-Nhydrochloric acid, dried over sodium sulfate and the solvent is removed.The residue is crystallized from methanol/ether. Yield 3.4 g; meltingpoint 245°-247° C.

EXAMPLE 15 Preparation of1-ethyl-6-(3-chlorophenyl)-4-oxo-1,4-dihydronicotinic acid

In a manner analogous to that described in Examples 1 and 2, fromm-chlorobenzaldehyde there was obtained2-(ethylaminomethylene)-5-(3-chlorophenyl)-3-oxo-4-pentenoic acid methylester, this was cyclized and saponified to give1-ethyl-6-(3-chlorophenyl)-4-oxo-1,4,5,6-tetrahydronicotinic acid,melting point 143°-145° C., and this was subsequently dehydrogenated togive 1-ethyl-6-(3-chlorophenyl)-4-oxo-1,4-dihydronicotinic acid, meltingpoint 212°-213° C.

EXAMPLE 16 Preparation of1-ethyl-6-(2,6-dichlorophenyl)-4-oxo-1,4-dihydronicotinic acid

In a manner analogous to that described in Examples 1 and 2, from2,6-dichlorobenzaldehyde there was obtained2-(ethylaminomethylene)-5-(2,6-dichlorophenyl)-3-oxo-4-pentenoic acidmethyl ester, this was cyclized and saponified to give1-ethyl-6-(2,6-dichlorophenyl)-4-oxo-1,4,5,6-tetrahydronicotinic acidand this was subsequently dehydrogenated to give1-ethyl-6-(2,6-dichlorophenyl)-4-oxo-1,4-dihydronicotinic acid, meltingpoint 200°-201° C.

EXAMPLE 17 Preparation of6-(4-chlorophenyl)-1-methyl-4-oxo-1,4-dihydronicotinic acid

In a manner analogous to that described in Examples 1 and 2, fromp-chlorobenzaldehyde there was obtained5-(4-chlorophenyl)-2-(methylaminomethylene)-3-oxo-4-pentenoic acidmethyl ester, melting point 114°-116° C., this was cyclized andsaponified to give6-(4-chlorophenyl)-1-methyl-4-oxo-1,4,5,6-tetrahydronicotinic acid,melting point 205°-206° C., and this was subsequently dehydrogenated togive 6-(4-chlorophenyl)-1-methyl-4-oxo-1,4-dihydronicotinic acid,melting point 275°-280° C. (decomposition).

EXAMPLE 18 Preparation of1-ethyl-6-(3-methyl-4-methylaminophenyl)-4-oxo-1,4-dihydronicotinic acid

In a manner analogous to that described in Examples 1 and 2, from3-methyl-4-methylamino-benzaldehyde there was obtained2-(ethylaminomethylene)-5-(3-methyl-4-methylaminophenyl)-3-oxo-4-pentenoicacid methyl ester, this was cyclized and saponified to give1-ethyl-6-(3-methyl-4-methylaminophenyl)-4-oxo-1,4,5,6-tetrahydronicotinicacid and this was subsequently dehydrogenated to give1-ethyl-6-(3-methyl-4-methylaminophenyl)-4-oxo-1,4-dihydronicotinicacid, melting point 243°-244° C.

EXAMPLE 19 Preparation of1-ethyl-4-oxo-6-(3-pyridyl)-1,4-dihydronicotinic acid

In a manner analogous to that described in Examples 1 and 2, fromnicotinaldehyde there was obtained2-(ethylaminomethylene)-3-oxo-5-(3-pyridyl)-4-pentenoic acid methylester, melting point 78°-80° C., this was cyclized and saponified togive 1-ethyl-4-oxo-6-(3-pyridyl)-1,4,5,6-tetrahydronicotinic acid,melting point 197°-199° C., and this was subsequently dehydrogenated togive 1-ethyl-4-oxo-6-(3-pyridyl)-1,4-dihydronicotinic acid, meltingpoint 209°-210° C.

1-Ethyl-4-oxo-6-(4-pyridyl)-1,4-dihydronicotinic acid, melting point268°-270° C., was prepared from isonicotinaldehyde in an analogousmanner.

EXAMPLE 20 Preparation of1-ethyl-6-(4-pyrrolidinophenyl)-4-oxo-1,4-dihydronicotinic acid

In a manner analogous to that described in Examples 1 and 2, from4-pyrrolidinobenzaldehyde there was obtained2-(ethylaminomethylene)-3-oxo-5-(4-pyrrolidinophenyl)-4-pentenoic acidmethyl ester, this was cyclized and saponified to give1-ethyl-4-oxo-6-(4-pyrrolidinophenyl)-1,4,5,6-tetrahydronicotinic acidand this was subsequently dehydrogenated to give1-ethyl-6-(4-pyrrolidinophenyl)-4-oxo-1,4-dihydronicotinic acid, meltingpoint 276°-278° C.

This acid can also be prepared as follows:

7.8 g. of 1-ethyl-4-oxo-6-(4-pyrrolophenyl)-1,4-dihydronicotinic acidmethyl ester are hydrogenated at room temperature with 8.5 g. of 5%palladium/carbon in 800 ml. of methanol. After removal of the catalyst,the mixture is evaporated to dryness and the residue is taken up inmethylene chloride. The organic solution is extracted with ice-cold 1-Nhydrochloric acid, the aqueous extract is neutralized with 1-N sodiumhydroxide and extracted with methylene chloride. After drying thesolution and evaporation, there are obtained 7.0 g. of1-ethyl-4-oxo-6-(4-pyrrolidinophenyl)-1,4-dihydronicotinic acid methylester having a melting point of 157°-159° C. (from methanol).

The ester can be saponified to the acid in a manner analogous to thatdescribed in Example 1.

EXAMPLE 21 Preparation of1-ethyl-6-(3-aminophenyl)-4-oxo-1,4-dihydronicotinic acid

1.25 g. of 1-ethyl-6-(3-nitrophenyl)-4-oxo-1,4-dihydronicotinic acid in60 ml. of dimethylformamide were hydrogenated at room temperature for 50minutes in the presence of 100 mg. of palladium/carbon (5%, w/w). Thecatalyst was filtered off, the solvent was removed and the residue wascrystallized from ethanol/ether. There were obtained 900 mg. of1-ethyl-6-(3-aminophenyl)-4-oxo-1,4-dihydronicotinic acid having amelting point of 145°-146.5° C.

The following Example illustrates a typical pharmaceutical preparationprovided by the present invention.

EXAMPLE A

Tablets weighing 120 mg. or 500 mg. and containing the followingingredients were produced:

    ______________________________________                                        1-Ethyl-4-oxo-6-phenyl-1,4-dihydro-                                                                10.0   mg.    --                                         nicotinic acid                                                                1-Ethyl-6-[4-(dimethylamino)-phenyl]-                                                              --            150  mg.                                   4-oxo-1,4-dihydronicotinic acid                                               Maize starch         50.0   mg.    160  mg.                                   Lactose              58.0   mg.    180  mg.                                   Talc                 1.5    mg.    7    mg.                                   Magnesium stearate   0.5    mg.    3    mg.                                                        120.0  mg.    500  mg.                                   ______________________________________                                    

I claim:
 1. A compound of the formula ##STR7## wherein R¹ is C₁₋₈ -alkyl, C₃₋₁₀ -cycloalkyl, C₃₋₁₀ -cycloalkyl-C₁₋₆ -alkyl, C₁₋₆ -alkoxy or C₁₋₆ -alkoxy-C₁₋₆ -alkyl; R² is hydrogen or C₁₋₆ -alkyl; R³ is phenethyl or styryl, which is substituted by R⁴, R⁵ and/or R⁶ ; R⁴ and R⁵, independently, are halogen, trifluoromethyl, hydroxy, C₁₋₆ -alkoxy, C₁₋₆ -alkylthio, C₁₋₆ -alkyl, amino, acylamino, C₁₋₆ -alkylamino, di-C₁₋₆ -alkylamino, nitro or a 5-membered or 6-membered heterocycle linked via ring N- or C-atom or R⁴ and R⁵ taken together are C₁₋₆ -alkylenedioxy; R⁶ is C₁₋₆ -alkoxy,or a pharmaceutically acceptable salt thereof.
 2. The compound of claim 1 wherein R³ is a substituted styryl group.
 3. The compound of claim 2 wherein said compound is 1-ethyl-6-(p-methoxystyryl)-4-oxo-1,4-dihydronicotinic acid.
 4. The compound of claim 1 wherein R³ is a substituted phenethyl group.
 5. A pharmaceutical composition comprising a compound of the formula ##STR8## wherein R¹ is C₁₋₈ -alkyl, C₃₋₁₀ -cycloalkyl, C₃₋₁₀ -cycloalkyl-C₁₋₆ -alkyl, C₁₋₆ -alkoxy or C₁₋₆ -alkoxy-C₁₋₆ -alkyl; R² is hydrogen or C₁₋₆ -alkyl; R³ is phenethyl or styryl, which is substituted by R⁴, R⁵ and/or R⁶ ; R⁴ and R⁵, independently, are halogen, trifluoromethyl, hydroxy, C₁₋₆ -alkoxy, C₁₋₆ -alkylthio, C₁₋₆ -alkyl, amino, acylamino, C₁₋₆ -alkylamino, di-C₁₋₆ -alkylamino, nitro or a 5-membered or 6-membered heterocycle linked via ring N- or C-atom or R⁴ and R⁵ taken together are C₁₋₆ -alkylenedioxy; R⁶ is C₁₋₆ -alkoxy,or a pharmaceutically acceptable salt thereof and a carrier material. 